The objective of this proposal is to examine the role of Insulin-like growth factor II (IGF-II) in the regulation of breast cancer growth. The fundamental hypothesis of this study is that IGF-II is an important and active participant in the process of malignant tumor progression in breast cancer. The insulin-like growth factors, IGF-I and IGF-II, are among the most potent mitogens for breast cancer epithelial cells yet described. Our preliminary data show that IGF-I is expressed in the stroma of normal breast, while IGF-II is expressed in the stroma of breast cancers. Co-culture studies have shown that cultured breast tumor fibroblasts which express IGF-II exert a marked mitogenic stimulus on breast tumor epithelium, and this effect is blocked by inhibiting IGF-II effects. Transfection studies show that induced overexpression of IGF-II in breast tumor epithelial cells confers marked phenotypic changes associated with malignant progression. This proposal will attempt to further define the role of IGF-II in breast cancer, and to test hypotheses aimed at inhibiting breast tumor growth. The goals of this study are: 1) To determine whether IGF-II expression is a prognostic indicator in breast cancer. 2) To examine the mechanism for the transition from IGF-I expression in normal breast stroma to IGF- II expression in breast tumor stroma. 3) To examine whether IGF-I overexpression is associated with the same phenotypic changes of malignant progression as IGF-II. 4) To clarify the role of the IGF-II receptor in IGF-II mediated malignant progression. 5) To attempt to use antisense RNA and oligonucleotides to inhibit IGF-II mediated stromal stimulation of breast cancer growth. 6) To evaluate the role of IGF-II in tumor cell invasion and chemotaxis. It is our hope that these studies will provide a better understanding of the role of IGF-II in breast cancer and help to identify new therapeutic targets for more rational and effective breast cancer treatment.